Research Article: Inhibition of NF-κB Pathway and Modulation of MAPK Signaling Pathways in Glioblastoma and Implications for Lovastatin and Tumor Necrosis Factor-Related Apoptosis Inducing Ligand (TRAIL) Combination Therapy

Date Published: January 30, 2017

Publisher: Public Library of Science

Author(s): Pi Chu Liu, Gang Lu, Yi Deng, Cheng Dong Wang, Xian Wei Su, Jing Ye Zhou, Tat Ming Chan, Xiang Hu, Wai Sang Poon, Javier S. Castresana.


Glioblastoma is a common malignant brain tumor and it is refractory to therapy because it usually contains a mixture of cell types. The tumor necrosis factor-related apoptosis inducing ligand (TRAIL) has been shown to induce apoptosis in a range of tumor cell types. Previously, we found that two human glioblastoma cell lines are resistant to TRAIL, while lovastatin sensitizes these glioblastoma cells to TRAIL-induced cell death. In this study, we investigated the mechanisms underlying the TRAIL-induced apoptosis in human glioblastoma cell lines by lovastatin. Furthermore, we have confirmed the anti-tumor effect of combination therapy with lovastatin and TRAIL in the subcutaneous brain tumor model. We showed that lovastatin significantly up-regulated the expression of death receptor 5 (DR5) in glioblastoma cell lines as well as in tumor-bearing mice with peri-tumoral administration of lovastatin. Further study in glioblastoma cell lines suggested that lovastatin treatment could inhibit NF-κB and Erk/MAPK pathways but activates JNK pathway. These results suggest that lovastatin sensitizes TRAIL-induced apoptosis by up-regulation of DR5 level via NF-κB inactivation, but also directly induces apoptosis by dysregulation of MAPK pathway. Our in vivo study showed that local peri-tumoral co-injection of lovastatin and TRAIL substantially reduced tumor growth compared with single injection of lovastatin or TRAIL in subcutaneous nude mice model. This study suggests that combined treatment of lovastatin and TRAIL is a promising therapeutic strategy to TRAIL-resistant glioblastoma.

Partial Text

Cancer is a class of diseases characterized by abnormal cell proliferation and survival, which are closely associated with dysregulated programmed cell death or apoptosis[1]. Apoptosis has gained considerable interest as a promising therapeutic target in cancer therapy. Signaling pathways that control the apoptotic process are therefore amenable to pharmacological intervention for tumor progression. One of the pathways that trigger the initiation of apoptosis is mediated through death receptors (DR) on the cell surface. Eight death receptors have been characterized so far, including TNF-related apoptosis-inducing ligand (TRAIL) receptor 1 (TRAILR1/DR4) and TRAILR2/DR5[2, 3]. The binding of natural death ligands (TNF cytokines) to DR4 or DR5 triggers the formation of death-inducing signaling complex (DISC)[4], which involves oligomerization of the DR and recruitment of Fas-associated death domain protein (FADD), proapoptotic caspase 8–10 as well as antiapoptotic cellular FADD-like IL-1β-converting enzyme-inhibitory protein (cFLIP), via homotypic protein-protein interactions between their death domains. The integration of the pro- and anti-apoptosis signals eventually leads to life-or-death decision making. In addition, decoy receptors (DcRs) that lack functional death domains also interact with death ligands, but do not trigger the formation of signaling complexes[3].

TRAIL resistance is found in several types of human glioblastoma[17]. Given its selectivity to target cancer cells, TRAIL-based therapies still hold clinical potentials to cancer treatment in conjunction with other therapies or clinically proven drugs[18–21]. Lovastatin, a commonly used cholesterol-lowering agent for prevention of atherosclerotic cardiovascular diseases[22], has been reported to inhibit proliferation of breast cancer cell lines[23] and induce apoptosis of ovarian cancer cells synergistically with doxorubicin[24]. We have previously reported that lovastatin sensitized human glioblastoma cells to TRAIL-induced apoptosis and caused cell cycle arrest at G0/G1 phase[7]. In the present study, we further investigated the molecular basis underlying the effects of lovastatin in the sensitization of TRAIL-mediated apoptosis in the glioblastoma cells, and tested pre-clinically the efficacy of combined treatment of lovastatin and TRAIL on subcutaneous brain tumors in mice. We found that lovastatin was sufficient to induce TRAIL-mediated apoptosis in the four human glioblastoma cells that are resistant to TRAIL-based chemotherapy. We also found that DR5 expression was increased upon lovastatin treatment which provides a molecular basis by which lovastatin enhances TRAIL-mediated apoptosis. In the in vivo subcutaneous brain tumor mice models, we found that DR5 expression was also elevated in the tumor tissue collected from mice that had received lovastatin through local peri-tumoral administration while remained unchanged in the normal tissues, indicating the specific effects of lovastatin on tumor tissues. Furthermore, in the mouse models, lovastatin in conjunction with TRAIL led to strikingly diminished tumor volumes as well as halted tumor growth. These findings suggest the roles of lovastatin in enhancing efficacies of TRAIL-based therapy.




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